Process of preparing oxo compounds of the cyclopentano-polyhydrophenanthrene series



Patented June 16, 1942 i PROCESS OF PREPARING OX COMPOUNDS OF THE 'CYCLOPENTANO-POLYHYDRO- PHENANTHR'ENE SERIES Max Bockmiihl,

Gustav Ehrhart,

Heinrich Ruschig, and Walter Aumiiller, Frankfort-on- Germany, assignors to Winthrop Chemical Company, Inc., New York, N. Y., a corporation of New York the Main Hochst,

No Drawing. Application August 9, 1938, Serial 4 Claims.

The present invention relates to'a process of preparing oxo-compounds of the cyclopen'tanopolyhydro-phenanthrene series.

In order to obtain the oxo-compounds corresponding with the amines of the cyclopentanopolyhydro-phenan'threne series the amine has hitherto been transformed into the corresponding alcohol by means of nitrous acid and the alcohol subsequently oxidized to form the 0x0- compound. The reaction of the amine with nitrous acid to form the alcohol is accompanied by a number of secondary reactions so that the yield of the alcohol desired is only very small. The further oxidation of the alcohol to form the oxo-compound is also very difficult, particularly in case that there are also other sensitive parts i-n the molecule, such as a double bond.

Now We have found that the amines of the cyclopentano polyhydro phenanthrene series may be transformed in a nearly quantitative reaction into the corresponding halogen-amine compounds with the aid cfhypchalogenous acid and these halogen-aminecom-pounds may readily be hydrolized, while splitting off hydrogen halide, to form the oxo-com pounds by hydrolysis of the imines-produced. It is suitable to perform the hydrolysis by means of dilute acids, for instance of dilute sulfuric acid.

The process may be carried out by isolating the halogen-amines after the reaction of the amines with hypohalcgenous acid (they are in part well crystallized compounds), splitting off hydrogen halide with the aid of alkalies and then transforming the i-minesproduced into the corresponding oxo-c'omp'ounds by hydrolysis by means of an acid. But the process may likewise be carried out in one operation, for instance by directly subjecting the reaction product from the amine and hypochlorous acid to hydrolysis by an acid or an alkali.

Hydrogen halide may be split oii from the halogen-amine compounds by means of the usual agents splitting ofi hydrogen, for instance by means of sodium alcoholate, sodium amide, caustic potash solution or pyridine.

As starting materials for the process of the present invention there may generally be used amines of the cyclopentano-polyhydro phenanthrene series, especially such compounds having the following general formula R- CH (Clin -N112- wherein R stands for a saturated or unsaturated cyclopentano-polyhydro-phenanthrene residue.

:1: stands for zero or 1 and 3 stands for zero, for 2.

The compounds bearing in 3-position of the cy- In Germany August 12, 1937 clopentano-polyhydro-phenanthrene residue the oXo-group or an esterified or non-esterified hy- .while vigorously shaking, into a solution of 1.66

grams of 3-hydroxyI'I-amino-androstene in "500 cc. of ether. The solution obtained is completely neutral. After having been filtered it is evaporated and the crystalline residue which consists of the 3-hydroxy-17--chlorylaminoandrostene is heated on the water bath for 45' minutes in cc. of absolute alcohol'tog'ether with 1.5 grams of sodium. Then the whole is poured into water containing sulfuric acid and the colloidal mixture is allowed to stand for one day. During this time the crude dehydro-androste'ne separates in flakes. It is introduced into ether and the residue of the ethereal solution which amounts to 1.2 grams is crystallized from ethyl acetate or aqueous alcohol. The final product melts at l36.5 C.

p The acetyl product melts at 167 C. to 168 -C.; the semi-carbazone of the acetyl product decomposes between 273 C. and 275 C.

(2) 13.4 grams of acetoxy-ternorcholenylamine are dissolved in 1.5 liters of ether and the solution is dried with the aid of potassium hydroxide. It is then filtered, some anhydrous sodium sulfate is added and the mixture is cooled to l5 C. Now 250 cc. of an ethereal solution of hypochlorous acid which contains 1.96 grams of hypochlorous acid and is likewise cooled to -15 C. is run in, while stirring. The solution obtained is evaporated under reduced pressure and the well crystallizable residue is the corresponding chloryl compound of the amine obtained in a nearly quantitative yield. The chloryl compound is introduced into 465 cc. of absolute alcohol, an alcoholic solution prepared from 8.8 grams of sodium and cc. of alcohol is added, and the whole is heated for 45 minutes on the water bath. The solution is then poured in water and the colloidal mixture is acidified with sulfuric acid. After some time the pregnenol(-3-)one(20) separates in the form of a white substance. The product is extracted with ether and the residue of the ethereal extract is crystallized from methanol. The yield amounts to 8 grams, the melting point is between 187 C. and 190 C.

(3) 22 grams of acetoxy-ternorcholanylamine are dissolved in methanol, 60 cc. of a methyl alcoholic caustic potash solution of 7.5 per cent strength are. added and ether is added to the whole. The ethereal solution is repeatedly washed with water, dried and in the presence of sodium sulfate 300 cc. of an ethereal solution containing 0.0094 gram of hypochlorous acid in 1 cc. are added. Distillation of the ether leaves the solid chloryl compound. This is dissolved in 320 cc. of absolute methanol without a further purification and the solution is heated to gentle boiling for 45 minutes together with a solution of 16 grams of sodium in 340 cc. of ethanol. The whole is then poured into dilute sulfuric acid and allowed to stand. The pregnanolone separates in flakes and is suitably extracted with ether. The crude pregnanolone obtained after the ether has been distilled melts at 142 C. After it has been recrystallized from dilute methanol the yield amounts to 14 grams.

(4) 1.4 grams of acetoxy-bisnorcholanylamine are dissolved in absolute ether and, while cooling with ice, the calculated quantity of an absolute ether solution of hypochlorous acid is run in. After the reaction has ceased and the ether has been distilled the chloryl compound of the 3-acetoxy-bisnorcholanylamine is obtained in a quantitative yield in the form of an amorphous substance. 200 cc. of absolute ethanol and a sodium ethylate solution prepared from 1.25 grams of sodium and 30 cc. of ethanol are added and the whole is boiled under reflux for 40 minutes. The mixture is then poured into dilute sulfuric acid and allowed to stand for some time while the bisnorcholane aldehyde separates in flakes; it is suitably isolated by extracting it with ether. After the hydroxy-bisnorcholane aldehyde has been recrystallized from dilute methanol it melts at 128 C. The yield is 0.9 gram.

(5) 6 grams of acetoxy-ternorcholenylamine are dissolved in 1.5 liters of ether and the solution is rapidly dried by means of potassium hydroxide. The solution is then filtered, some anhydrous sodium sulfate is added and the mixture is cooled to 15 C. The calculated quantity of the ethereal solution of hypochlorous acid which is likewise cooled to -15 C. is now slowly run in. By this operation first a small quantity of the hydrochloride of acetoxy-ternorcholenylamine separates. After addition of the calculated quantity of hypochlorous acid the at first strongly alkaline reaction of the solution becomes neutral. About 59 cc. of an ethereal solution of hypochlorous acid containing 14.8 milligrams of hypochlorous acid in 1 cc. are required.

The solution is at once filtered and evaporated under reduced pressure. The residue constitutes 5.4 grams of the corresponding chloryl compound. It is oily but crystallises when triturated. It is ground together with 40 cc. of an alcoholic caustic potash solution of 10 per cent strength in which operation the separation of potassium chloride sets in at once and ammonia is split off. After 24 hours the reaction is finished. The solution is poured into water, acidified with sulfuric acid and it is then extracted with ether. residue of the ethereal solution contains 3.5 grams of the desired ketone compound.

(6) 64 cc. of an ice-cold ethereal solution of hypochlorous acid containing 0.62 gram of hypochlorous acid are run, while vigorously shaking, at -5 C. and in the presence of sodium sulfate into a solution of 3.32 grams of 3-oxo-l'7-aminoandrostene in 1 liter of absolute ether. The solution has a neutral reaction. It is evaporated under reduced pressure, the residue is heated under reflux for 45 minutes with a sodium alcoholate solution prepared from 3 grams of sodium and 210 cc. of absolute alcohol, the reaction solu- The tion is poured into water acidified by means of sulfuric acid and the colloidal mixture is allowed to stand for 24 hours. The whole is then etherified, the residue is distilled under a strongly reduced pressure from the ethereal solution (boiling point C. to 210 C. under a pressure of 0.05 millimeter) and the distillate is redissolved in aqueous acetone. The androstendionemelts at 167 C.

We claim:

1. The process which comprises causing an amine of the following general formula:

[CH3 R- (3H (Climb-BN1 wherein R stands for a member of the group consisting of saturated and unsaturated cyclopentano polyhydro phenanthrene radicals, X stands for a member selected from the group consisting of 0 and 1, and Y stands for a member selected from the group consisting of 0, 1 and 2 to react with hypohalogenous acid, splitting off hydrogen halide from the halogen amine compound thus obtained and hydrolyzing the imine thus formed.

2. The process which comprises causing an amine of the following general formula:

(EH3 R-LCH om)..Nm wherein R stands for a member of the group consisting of saturated and unsaturated cyclopentano-polyhydro-phenanthrene radicals bearing in 3-position a member of the group consisting of oxygen, hydroxyl and esterified hydroxyl, X stands for a member selected from the group consisting of 0 and 1, and Y stands for a member selected from the group consisting of 0, 1 and 2 to react with hypochlorous acid, splitting off hydrogen chloride from the halogen amine compound thus obtained and hydrolyzing the imine thus formed.

3. The process which comprises causing an amine of the following general formula:

wherein R stands for a member of the group consisting of saturated and unsaturated cyclopentano polyhydro phenanthrene radicals, X stands for a member selected from the group consisting of 0 and 1, and Y stands for a member selected from the group consisting of 0, 1 and 2 to react with hypochlorous acid, splitting ofi hydrogen chloride from the halogen amine compound thus obtained andhydrolyzing the imine thus formed.

4. The process which comprises causing an amine of the following general formula: 

